PROJECT SUMMARY/ABSTRACT: In genetically heterogeneous humans, differing combinatorial subsets drawn from a larger overall pool of potential disease susceptibility genes may contribute to type-1 diabetes (T1D) pathogenesis by eliciting perturbations at differing operational points within a common set of immunoregulatory pathways. This genetic complexity is illustrated by the previous observation that nominally resistant mouse strains can carry gene variants which when expressed in the proper combinatorial context contribute more strongly to T1D development than the corresponding allele from disease susceptible NOD mice. We propose that T1D developing in progeny from outcross/backcross between NOD and nondiabetic strains, wherein susceptibility genes come from both parental genomes, more accurately reflects the situation in humans. This proposal focuses on a potent likely single recessively-acting diabetogenic gene discovered in the distal region of Chromosome (Chr.) 11 of a disease resistant C57BL/6J (B6) stock congenic for the NOD derived H2g7 MHC haplotype (B6.H2g7). This B6.H2g7 origin gene in tight linkage with the marker D11Mit48 acts through CD4 T cells to more strongly promote pathogenic activation of diabetogenic CD8 T cells than the NOD allelic variant. The discovery of a single gene exerting strikingly divergent effects on how CD4 T cells support pathogenic CD8 T cells presents a unique opportunity to better understand and design treatments for immunological tolerance induction defects underlying T1D susceptibility. The current proposal seeks to (1) identify the Chr.11 gene that supports or suppresses pathogenic CD8 T-cell activation to determine whether it may be targeted for disease prevention and (2) define which CD4 T cell population is directly controlled by the D11Mit48-linked locus to regulate diabetogenic CD8 T cells.